AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5563-8. doi: 10.1016/j.bmcl.2012.07.012. Epub 2012 Jul 15.
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
本文描述了一种腈类化合物 4 的发现，该化合物是组织蛋白酶 K（Cat K）的有效抑制剂，在狗体内具有良好的生物利用度。该化合物被用于在体内狗 PD 模型中证明靶标结合和 Cat K 抑制。由于与 hERG 离子通道抑制的差距太小，该化合物不适合作为临床候选药物，因此一个优化计划旨在寻找苯并噻唑基团的等排体或取代基，从而发现了 20、24 和 27；这三种化合物均无 hERG 抑制作用。
